ORPHA: 221061; DO: 0060670;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p13 | Cerebral cavernous malformations-2 | 603284 | Autosomal dominant | 3 | CCM2 | 607929 |
A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-2 (CCM2) is caused by heterozygous mutation in the CCM2 gene (607929) on chromosome 7p13.
Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM2 pathogenesis; see PATHOGENESIS and MOLECULAR GENETICS sections.
Cerebral cavernous malformations are vascular malformations, mostly located within the CNS, characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs usually present clinically during the third to fifth decade of life, resulting in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits (summary by Denier et al., 2004).
For a discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860).
Ahdab et al. (2008) reported 2 sibs with CCM2 confirmed by genetic analysis. The 57-year-old proband presented with generalized tonic-clonic seizures and status epilepticus. Brain MRI showed multiple rounded gradient echo hypointense signals mainly in the right frontotemporal region, consistent with CCM. He also had numerous small erythematous 2 to 3-mm macules that blanched on his palms. The pattern was consistent with capillary telangiectasia. His 60-year-old sister developed mild gait ataxia associated with multiple supra- and infratentorial CCMs on brain MRI. She also had palmar telangiectasia. Their mother reportedly had episodes of diplopia and vertigo and also had the same palmar lesions.
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1 (604214), CCM2/malcavernin, or PDCD10 (609118) protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient and normal brain endothelium from a CCM2 patient stained positively for KRIT1 and CCM2/malcavernin, respectively. Pagenstecher et al. (2009) suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation.
Craig et al. (1998) reported analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. Linkage to new loci, CCM2 at 7p15-p13 and CCM3 (603285) at 3q25.2-q27, was demonstrated. Multilocus analysis yielded a maximum lod score of 14.11, with 14% of kindreds linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3, with highly significant evidence for linkage to 3 loci; linkage to 3 loci was supported with an odds ratio of 2.6 x 10(5):1 over linkage to 2 loci, and 1.6 x 10(9):1 over linkage to 1 locus. Multipoint analysis among families with high posterior probabilities of linkage to each of the 3 loci refined the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these 3 loci can account for inheritance of CCM in all kindreds studied. Significant locus-specific differences in penetrance were identified.
The transmission pattern of CCM2 in the families reported by Liquori et al. (2003) was consistent with autosomal dominant inheritance.
Liquori et al. (2003) sequenced positional candidate genes in the 7p region for mutations in CCM2. One of these genes, the CCM2 gene, which they called MGC4607, was chosen because its translation product protein encodes a putative phosphotyrosine-binding (PTB) domain. The same domain is found in ICAP1-alpha (607153), a binding partner of the KRIT1 gene (604214). In a panel of 27 probands without a KRIT1 mutation, Liquori et al. (2003) detected 8 different heterozygous mutations in the CCM2 gene (see, e.g., 607929.0001-607929.0004).
In 2 (14%) of 14 unrelated patients with sporadic CCM and multiple lesions, Felbor et al. (2007) identified a respective deletion in the CCM2 gene using multiplex ligation-dependent probe amplification. One of the deletions involved the entire coding region of the CCM2 gene.
In 8 (13%) of 63 U.S. families with CCM, Liquori et al. (2007) identified a 77.6-kb deletion encompassing exons 2 through 10 in the CCM2 gene (607929.0009).
Liquori et al. (2008) reported 6 additional CCM families from the United States with the 77.6-kb CCM2 deletion. Haplotype analysis, which included the previously reported families with this deletion, indicated a founder effect. This deletion was not present in 24 Italian families with CCM, indicating that it is specific to a certain cohort of patients. Among the 24 Italian families with CCM, Liquori et al. (2008) identified 4 deletions and 1 duplication in the CCM2 gene.
By use of repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, Akers et al. (2009) identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. Akers et al. (2009) suggested that CCM lesion genesis may require complete loss of function for one of the CCM genes.
Gallione et al. (2011) identified a founder mutation in the Ashkenazi Jewish population that affects mRNA splicing of the CCM2 gene causing cerebral cavernous malformations (607929.0010).
In 27 unrelated patients with CCM and heterozygosity for the 77.6-kb deletion (607929.0009) encompassing exons 2-10 of the CCM2 gene, Gallione et al. (2022) sequenced 10 kb upstream and downstream of the deletion to evaluate for a shared haplotype. SNP analysis demonstrated a shared haplotype among all 27 patients. The deletion was shown to be due to a recombination between an AluSx and an AluSg sequence, which, although highly homologous, are not identical. Genealogy studies showed that 5 of the families may share a single common ancestor.
Bergametti et al. (2020) identified 6 heterozygous mutations in the CCM2 gene (607929.0007; 607929.0011-607929.0015) in 7 unrelated patients with CCM. The mutations were identified by sequencing of 3 genes associated with cerebral cavernous malformations. Coimmunoprecipitation studies with each of the mutations resulted in loss of interaction between CCM1 and CCM2.
Ahdab, R., Riant, F., Brugieres, P., Roujeau, J.-C., Hodel, J., Hosseini, H. Familial cerebral cavernomatous malformations associated with palmar capillary telangiectasias. Neurology 71: 861-862, 2008. [PubMed: 18779516] [Full Text: https://doi.org/10.1212/01.wnl.0000325474.61048.ae]
Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum. Molec. Genet. 18: 919-930, 2009. [PubMed: 19088123] [Full Text: https://doi.org/10.1093/hmg/ddn430]
Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations. J. Med. Genet. 57: 400-404, 2020. [PubMed: 31937560] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106401]
Craig, H. D., Gunel, M., Cepeda, O., Johnson, E. W., Ptacek, L., Steinberg, G. K., Ogilvy, C. S., Berg, M. J., Crawford, S. C., Scott, R. M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C. T. C., Mettler, G., Beis, M. J., Fryer, A., Awad, I. A., Lifton, R. P. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Molec. Genet. 7: 1851-1858, 1998. [PubMed: 9811928] [Full Text: https://doi.org/10.1093/hmg/7.12.1851]
Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am. J. Hum. Genet. 74: 326-337, 2004. [PubMed: 14740320] [Full Text: https://doi.org/10.1086/381718]
Felbor, U., Gaetzner, S., Verlaan, D. J., Vijzelaar, R., Rouleau, G. A., Siegel, A. M. Large germline deletions and duplication in isolated cerebral cavernous malformation patients. Neurogenetics 8: 149-153, 2007. [PubMed: 17211633] [Full Text: https://doi.org/10.1007/s10048-006-0076-7]
Gallione, C. J., Detter, M. R., Sheline, A., Christmas, H. M., Lee, C., Marchuk, D. A. Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene. Hum. Genet. 141: 1761-1769, 2022. [PubMed: 35488064] [Full Text: https://doi.org/10.1007/s00439-022-02458-5]
Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A. A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations. Genet. Med. 13: 662-666, 2011. [PubMed: 21543988] [Full Text: https://doi.org/10.1097/GIM.0b013e318211ff8b]
Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am. J. Hum. Genet. 73: 1459-1464, 2003. [PubMed: 14624391] [Full Text: https://doi.org/10.1086/380314]
Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A. Deletions in CCM2 are a common cause of cervical cavernous malformations. Am. J. Hum. Genet. 80: 69-75, 2007. [PubMed: 17160895] [Full Text: https://doi.org/10.1086/510439]
Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F. Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9: 25-31, 2008. [PubMed: 18060436] [Full Text: https://doi.org/10.1007/s10048-007-0109-x]
Pagenstecher, A., Stahl, S., Sure, U., Felbor, U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Molec. Genet. 18: 911-918, 2009. [PubMed: 19088124] [Full Text: https://doi.org/10.1093/hmg/ddn420]